Piperazine and morpholine-like compounds are relevant in the chemical industry, particularly the pharmaceutical industry, and are building blocks or components for a number of pharmacologically active substances, particularly in enhancing the bioavailability and/or antagonistic adhesion of pharmaceuticals.
Piperazine itself can be produced as one of the products in the reaction of 1,2-dichloroethane or ethanolamine with ammonia, whereby piperazine is separated from the product streams, possibly containing ethylenediamine, diethylenetriamine, and other related linear and cyclic analogs. Piperazine is consequently inexpensive relative to its bridged analogs. Likewise, morpholine may be produced by the dehydration of diethanolamine with sulfuric acid, and is similarly inexpensive due to the scalability of its industrial synthesis.
Bridged analogs of morpholine and piperazine are very interesting alternatives to their unbridged analogs, particularly for their case of exchange with piperazine and/or morpholine, and because such bridged species, due to their restrained degrees of freedom and translation, may provide more efficiently binding products upon such substitution of the non-bridged analog for the bridged. However, most known routes to these bridged analogs of piperazine, morpholine, and other heteropolycycles are not commercially viable due to the high costs from any of extensive synthetic steps, complicated and numerous separations, and high material and equipment outlays of the known alternative processes.
Numerous academic and industrial research groups have pursued new or improved methods for synthesizing such compounds, particularly methods which are scalable. Amongst a number of useful and relevant bridged analogs of piperazine are 3,8-diazabicyclo[3.2.1]octanes, 2,5-diazabicyclo[2.2.1]heptanes, 3,6-diazabicyclo[3.1.0]hexanes,
3,6-diazabicyclo[3.1.1]heptane, and 2,5-diazabicyclo[2.2.2]octanes,

Based on the numerous known syntheses discussed in the literature, summarized in U.S. Appl. Ser. No. 62/057,939, it is clear that there is a need for alternate synthetic approaches to heteropolycycles, which may employ cheaper starting materials and/or reduce the overall steps to the end product.
A legalistic search into whether and how the scope of the inventions reported herein could be affected by publications imputed by international patent laws to be known to those of ordinary skill in the art (although such publications were not known to the inventors, nor impacted the formative thinking of the invention), revealed certain publications which warrant pre-emptive discussion.
One publication discloses the reaction of a 1:2,5:6-bisepoxyoctadiene with methylamine to form a heteromonocycle, which is subsequently acetylated with acetic anhydride. Michel, P.; Rassat, A. An Easy Access to 2,6-Dihydroxy-9-azabicyclo[3.3.1]nonane, a Versatile Synthon. J. Org. Chem. 2000, 65, 2572-2573. Michel produces only a polycycle having a single heteroatom, nitrogen, integrated into the polycyclic backbone (skeleton), and is silent on modifying the products to have even two heteroatoms in the ring backbone, instead seeking to produce, inter alia, nitroxide biradicals. Another reference of this type discloses the formation of heteropolycycle by the reaction of a 1:2,5:6-bisepoxyoctadiene with an alkylamine, but fails to disclose or suggest the formation of a heteropolycycle having more than one heteroatom, instead limiting its disclosure to the complicated enantiomers and spectroscopic properties of the 9-azabicyclo[3.3.1]nonanes. Bieliunas, V.; Rackauskaite, D.; Orentas, E.; Stoncius, S. Synthesis, Entiomer Separation, and Absolute Configuration of 2,6-Oxygenated 9-Azabicyclo[3.3.1]nonanes. J. Org. Chem. 2013, 78, 5339-5348.
Another publication discloses the reaction of a derivative of a di-epoxidized amide form of diallylamine, as a small portion of much more complicated liposidomycin-analogs at pg. 3930 (29a:29b to 30a:30b in Scheme 4). Sarabia, F.; Martin-Ortiz, L.; Lopez-Herrera, F. J. A Convergent Synthetic Approach to the Nucleoside-Type Liposidomycin Antibiotics. Org. Lett. 2003, 5(21), 3927-3930. Not only does Sarabia not produce a polycycle, but rather only a monoheterocycle, the reaction in question would not have lent itself to further cyclization within the scope of this invention, even if such a reaction were suggested and would have been reasonably expected to function.
A further reference discloses separate reactions of a derivative of 1:2,4:5-bisepoxypentane with an alkylamine to give various dihydroxypiperidines. Concellon; J. M.; Rivero, I. A.; Rodriguez-Solla, H.; Concellon, C.; Espana, E.; Garcia-Granda, S.; Diaz, M. R. Totally Selective Synthesis of Enantiopure (3S,5 R)-4-Amino-3,5-dihydroxypiperidines from Aminodiepoxides Derived from Serine. J. Org. Chem. 2008, 73(15), 6048-6051. Concellon, however, does not suggest further cyclization, nor that a target product should include two or more heteroatoms in the backbone of any such heteropolycycle.
A further reference discloses a reaction of two epoxides in the ultimate formation of a heteropolycycle with two or more heteroatoms in the ring backbone. Breuning, M.; Steiner, M.; Mehler, C.; Paasche, A.; Hein, D. A Flexible Route to Chiral 2-endo-Substituted 9-Oxabispidines and Their Application in the Enantioselective Oxidation of Secondary Alcohols. J. Org. Chem. 2009, 74(3), 1407-1410. However, Breuning does not disclose reacting a bisepoxide, nor a single-pot reaction of two epoxides upon a single starting molecule.
Similarly, WO 2006/137769 A1 discloses the reaction of a bisepoxidated analog of diallyl amine, and ultimately forms a heteropolycycle from the heteromonocyclic diol intermediate. However, WO 2006/137769 A1 discloses only oxadiazabispidine analogs which have nitrogen heteroatoms introduced into to heteropolycyclic backbone without the use of an (amine) nucleophile, i.e., with a sulfonamide and epichlorohydrin, based on the particular reaction sequence suggested therein, e.g., at pg. 18. Bisepoxides lacking hydroxyl substituents are not disclosed or suggested by WO 2006/137769 A1, nor is the production of a heteropolycycle into which each nitrogen is introduced by an amine nucleophile. WO 2013/050938 A1 also discloses subject matter related to the reaction of an N-protected epoxidized analog of diallylamine, producing oxadiazabispidine analogs, i.e., heteropolycycles. However, WO 2013/050938 A1 likewise describes the reaction of a protected starting material, already having a nitrogen in the backbone chain. Unlike the claimed embodiments of the present invention, which introduce all of the nitrogen heteroatoms into the skeleton of the claim, WO 2013/050938 A1 discloses already introducing a nitrogen into the heteropolycycle before the reaction of the bisepoxide, see, e.g., pg. 47-48. Moreover, WO 2013/050938 A1 does not disclose or suggest a reaction which introduces all heteroatoms, or at least all nitrogen heteroatoms, into the polycyclic backbone after reacting the bisepoxide. US 2009/0326221 A1 and US 2010/0160626 A1 suffer from the same fundamental flaws. Moreover, WO 2006/137769 A1 and its kin disclose only oxygenated analogs of bispidine, and do not suggest larger or smaller rings, nor rings having 2, 4, or more heteroatoms in the heteropolycyclic backbone.
Another set of references discloses the reaction of certain sugar bisepoxides with alkylamines to obtain polyhydroxylated azepanes. Orwig, S. D.; Tan, Y. L.; Grimster, N. P.; Yu, Z.; Powers, E. T.; Kelly, J. W.; Lieberman, R. L. Binding of 3,4,5,6-Tetrahydroxyazepanes to the Acid-β-glucosidase Active Site: Implications for Pharmacological Chaperone Design for Gaucher Disease. Biochemistry 2011, 50, 10647-10657; WO 95/022526 A1. However, none of these iditol references provides a motivation to create a polycyclic compound from the obtained azepanes, nor any indication that such further processing would be achievable. U.S. Pat. No. 6,462,193 B1 is of similar deficient character in this regard.
A further publication discloses a reaction of a bisepoxide with a nucleophile. Paul, R.; Tchelitcheff, S. Diethylenic hydrocarbons: II. Synthesis of 3,5-dihydroxy-1-substituted piperidines from 1,4-pentadiene. Bull. Soc. Chim. France 1948, 10, 896-900. Paul, however, only produces a heteromonocycle, and makes no mention of polycyclic compounds. Furthermore, were the piperidine monocycles suggestive of polycycles, more than a half century has passed since Paul's publication, a substantially long period of time.
A 2014 reference discloses a method of producing 3,8-diazabicyclo[3.2.1]octane by an oxidative route from 1,5-hexadiene, but its method does not employ epoxidation and requires a sulfonamide-protected amine for the initial ring opening step. Shainyan, B. A.; Moskalik, M. Y.; Astakhova, V. V.; Schilde, U. Novel design of 3,8-diazabicyclo[3.2.1]octane framework in oxidative sulfonamidation of 1,5-hexadiene. Tetrahedron 2014, 70, 4547-4551.
A further 2014 reference discloses a reaction of a bis-epoxide with an amine nucleophile to form a cyclic species, but the post-epoxidation reaction sequence disclosed therein does not further cyclize the product of the epoxide opening and furthermore forms a heteropolycycle having only a single heteroatom in its carbon backbone. Grenning, A. J.; Snyder, J. K.; Porco, Jr., J. A. Org. Lett. 2014, 16, 792-795.